Decreased tumor necrosis factor production during the initial stages of infection correlates with survival during murine gram-negative sepsis.
Secretion of tumor necrosis factor (TNF)/cachectin occurs during gram-negative bacterial sepsis in response to macrophage stimulation by lipopolysaccharide (endotoxin) and may play an early pivotal role in the subsequent host response. We sought to determine whether administration of: (1) murine monoclonal antibody directed against endotoxin, (2) steroids, or (3) antimicrobial agents would abrogate TNF production and whether the protective capacity would correlate with TNF levels in an experimental model of murine gram-negative bacterial sepsis. Mice were pretreated with anti-lipopolysaccharide monoclonal antibody, gentamicin sulfate, hydrocortisone, or saline and were then challenged with a lethal dose of intraperitoneal Salmonella minnesota. Murine serum TNF levels were measured by the L929 fibroblast cytotoxicity assay. Both gentamicin and anti-lipopolysaccharide monoclonal antibody significantly enhanced survival, and TNF activity at 1.5 and 3 hours was significantly suppressed in animals receiving these agents compared with animals that received either steroids or saline. We conclude that agents such as gentamicin, which inhibits bacterial replication, or monoclonal antibodies, which may neutralize lipopolysaccharide, indeed enhance survival, and survival was correlated with a significant reduction in circulating TNF during the early stages of infection.
Mayoral
J L
JL
Department of Surgery, University of Minnesota, Minneapolis.
Schweich
C J
CJ
Dunn
D L
DL
D000818:Animals; D000911:Antibodies, Monoclonal; D005839:Gentamicins / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D012475:Salmonella; D012481:Salmonella Infections, Animal / Q000378:metabolism* / Q000401:mortality; D012965:Sodium Chloride; D013534:Survival; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D005839:Gentamicins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D012965:Sodium Chloride; D006854:Hydrocortisone